Oxidative stress is caused by disturbances to the normal redox state within cells. An imbalance between routine production and detoxification of reactive oxygen species such as peroxides and free radicals can result in oxidative damage to the cellular structure and machinery.
Oxygen poisoning or toxicity is caused by high concentrations of oxygen that may be damaging to the body and increase the formation of free-radicals and other structures such as nitric oxide, peroxynitrite, and trioxidane. Normally, the body has many defense systems against such damage but at higher concentrations of free oxygen, these systems are eventually overwhelmed with time, and the rate of damage to cell membranes exceeds the capacity of systems which control or repair it. Cell damage and cell death then results.
Qualitative and/or quantitative disruptions in the transport of oxygen to tissues result in energy disruption in the function of red cells and contribute to various diseases such as hemoglobinopathies. Hemoglobinopathy is a genetic defect that results in abnormal structure of one of the globin chains of the hemoglobin molecule. Common hemoglobinopathies include thalassemia and sickle-cell disease. Thalassemia is an inherited autosomal recessive blood disease. In thalassemia, the genetic defect results in reduced rate of synthesis of one of the globin chains that makes up hemoglobin. While thalassemia is a quantitative problem of too few globins synthesized, sickle-cell disease is a qualitative problem of synthesis of an incorrectly functioning globin. Sickle-cell disease is a blood disorder characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in their restricted movement through blood vessels, depriving downstream tissues of oxygen. In both thalassemia and sickle cell anemia, pathology can result from reactive oxygen species caused by the disruptions in oxygen transport.
Another disorder caused by reactive oxygen species is nephropathy, contrast induced nephropathy (CIN) or contrast nephropathy (CN). Recent research implicates hypoxic tubular injury in the pathophysiology of contrast nephropathy. While intrarenal hypoxia can be caused by systemic transient hypoxemia, increased blood viscosity, and a leftward shift of the oxygen-hemoglobin dissociation curve, imbalance between oxygen demand and supply plays a major role in hypoxic damage to the outer medulla of the kidney caused by contrast media. The outer medulla is normally in a condition of low oxygen tension, due to a limited oxygen supply in the region, a high local metabolic rate, and high oxygen demand, resulting from active salt reabsorption by medullary thick ascending limbs of Henle's loop. Outer medullary physiologic hypoxia is negatively impacted by radiologic contrast agents. Increased metabolic activity and oxygen consumption (due to osmotic diuresis and increased salt delivery to the distal nephron) occurs because the blood flow to this region and the oxygen supply actually increase (Heyman, S N et al, Invest. Radiol. (1999), 34 (11) 685-91 and Garofalo A S, Ren. Fail. (2007) 29 (2), 121-31).
Contrast agents or dyes, including iodinated contrast solutions, are solutions opaque to x-rays that enable the circulatory system arteries and veins to be visualized, and that enhance the image being obtained. Contrast agents are frequently used in medical procedures. They are frequently administered to patients undergoing radiographic investigations, such as fluoroscopy, x-ray, magnetic resonance, ultrasound imaging and diagnostic angiography. Contrast solutions may also be used in patients undergoing coronary angioplasty or other cardiac catheterization procedures, peripheral vessel studies and placement of pacemaker leads. Delivery of the contrast media into a patient's vasculature enables the vasculature of different organs, tissue types, or body compartments to be more clearly observed or identified.
Radiographic contrast agents can be grouped into two main categories: positive contrast agents and negative contrast agents. Positive contrast media are radiopaque (appearing lighter than surrounding structures) due to their ability to attenuate the X-ray beam. Positive contrast agents contain elements with high atomic weights, (such as iodine, bromine, gadolinium, and barium) which add density to the tissues of interest. Negative contrast agents are radiolucent (darker than surrounding structures) because of their inability to attenuate the X-ray beam. Air and water are examples of negative contrast agents.
Intravascular contrast agents typically comprise iodinated benzene ring derivatives that are formulated as sodium or meglumine salts. The multiple iodine molecules contained within the contrast agent are responsible for the additional attenuation of X-rays in excess of that caused by blood alone. The amount of radiopacity that is generated by a particular contrast agent is a function of the percentage of iodine in the molecule and the concentration of the contrast media administered. The iodine content in different radiographic contrast media can vary from 11% to 48%. With most contrast solutions the iodine content is also proportional to the osmolarity of the contrast agent. Iodinated contrast agents are classified as ionic or high osmolar contrast media (HOCM) or nonionic or low osmolar contrast media (LOCM). The osmolarity of the contrast agent can lead to significant side effects in clinical practice. In general, the lower the osmolarity of the agent the less side effects will occur in the patient.
One of the adverse side effects associated with the use of radiographic contrast media includes nephrotoxicity. In particular, contrast medium-induced nephrotoxicity is known to be an iatrogenic cause of acute renal failure in some patients. It has been reported that use of contrast media is the third most common cause of new onset renal failure in hospital patients. Patients who experience nephrotoxicity may experience changes in serum creatine, or creatine clearance, at about one to five days after receiving the contrast medium. Consequences may be dramatic and can lead to irreversible renal damage and transient or long-term dialysis.
Mild transient decreases in renal function occur after contrast administration in almost all patients. Whether a patient develops clinically significant acute renal failure depends on the presence or absence of certain factors. Factors that may predispose a patient for developing acute renal failure include pre-existing baseline renal insufficiency, diabetes mellitus, cardiovascular disease, including congestive heart failure, aging, and conditions characterized by depletion of effective circulatory volume. Higher doses of contrast media may also increase the risk of contrast nephropathy (CN). Other risk factors include reduced effective arterial volume due for example to dehydration, nephrosis or cirrhosis or concurrent use of potentially nephrotoxic drugs such as nonsteroidal anti-inflammatory agents and ACE (angiotensin-converting enzyme) inhibitors. Patients with preexisting renal impairments and diabetes mellitus have a substantially higher risk of CN than patients with renal impairments alone.
Patients undergoing coronary procedures where contrast enhanced imaging for the interventions are used are at particularly at risk of contrast induced nephropathy. Prevention and mitigation of renal failure after the administration of contrast agent is difficult to achieve. Hydration has been reported to ameliorate contrast nephropathy in chronic renal failure patients (Solomon et al., N. Engl. J. Med (1994) 331:1416-20). Ramesh J. et al., J Assoc Physicians India. (2006) 54:449-52 suggest that the use of N-Acetyl cysteine could be beneficial for the reduction of renal failure induced by contrast agents.
Accordingly, the problems associated with contrast nephropathy have been a limiting factor to the extent that these advanced angioplasty procedures can be used, particularly in vulnerable populations.
Other causes of nephropathy include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs), amphotericin B, cisplatin, methotrexate, acyclovir, gentamicin, ACE inhibitors, other nephrotoxic drugs, products of tumor lysis syndrome and products of rhabdomyolosis.
An additional cause of oxidative stress is radiation. Radiation is known to produce various reactive oxygen species (ROS) in biological systems such as superoxide, hydrogen peroxide and hydroxyl radical and cause various types of tissue damage due to free radical reactions (Adler V. et al., Oncogene 1999 Nov. 1; 18 (45):6104-11). Reactive oxygen species and free radicals react with nucleic acids, lipids, proteins and carbohydrates and induce damage. Cytoplasmic irradiation can result in damage to nuclear DNA. Experiments with free radical scavengers have shown this DNA damage is dependent on ROS generation (Spitz D R, et al. “Metabolic Oxidation/Reduction Reactions and Cellular Responses to Ionizing Radiation: A Unifying Concept in Stress Response Biology.” Cancer and Metastasis Reviews. (2004) 23:311-322; and Wu L J, et al., “Targeted Cytoplasmic Irradiation with Alpha Particles Induces Mutations in Mammalian Cells.” Proceedings of the National Academy of Sciences. (1999) 96 (9): 4959-4964).
Exposure to ionizing radiation (such as X-rays, gamma rays and alpha- or beta-radiation) can cause damage to cells. The damage can result in cell death (e.g. through apoptosis), or can cause genetic changes in the cell, resulting in unchecked cell proliferation and cancer. While in general, exposure to such radiation is therefore undesirable, the administration of carefully regulated doses is an accepted treatment for certain cancers. By targeting the radiation to a tumor, cells can be destroyed. A frequent complication of radiotherapy is the irradiation of normal tissues surrounding the cancerous tissues. Such normal tissues are often damaged by the radiation resulting in undesired injury to normal cells and tissues, which can have severe consequences for the affected patient.
Radioprotective agents, also known as radioprotectors, are defined as agents that protect cells or living organisms from deleterious cellular effects of exposure to ionizing radiation. These deleterious cellular effects include damage to cellular DNA, such as DNA strand break, disruption in cellular function, cell death and/or carcinogenesis. The mechanism of the protective effect may at least be partially due to radical scavenging properties and cell cycle modulating properties of the radioprotective agents. These agents, administered prior to, during, and/or after exposure to radiation would eliminate or reduce the severity of deleterious cellular effects caused by exposure to environmental ionizing radiation such as those resulting from a nuclear explosion, a spill of radioactive material, close proximity to radioactive material and the like.
In addition, these agents are believed to provide a selective protection of normal cells and non-cancerous cells during cancer therapy. For example, these agents, administered to the cancer patient prior to or during radiation therapy, will be absorbed by normal, non-cancerous cells to provide a protective effect. However, the radioprotective agents will be absorbed to a lesser or no effect by tumor cells due to their different vascularity and their other known biological differences from normal cells.
The treatment of malignant tumors through the use of radiation is often limited by damage to non-tumor cells. Damage to the non-tumor cells can exceed the effectiveness of the radiation therapy. The main consideration in establishing radiation doses for cancer radiotherapy is the assessment of tolerance of the most radiosensitive normal tissue or organ in the treatment field. Often the maximum tolerable doses are insufficient to eradicate the tumor. Thus the use of a radioprotective agent would greatly increase the tolerable dose, and therefore the prospects of eradication of tumors and treatment of cancer. Cell survival and adaptation to an environment containing radiation can mainly depend on the ability of cells to maintain optimal function in response to free radical-induced damage at the biochemical level. There remains an acute need for non-toxic and effective radio-protectors.
Exposure to radiation can also occur in other ways, including exposure to normal background levels of radiation (such as cosmic rays or radiation due to naturally occurring isotopes present in the earth) or elevated environmental radiation (including occupational exposure of workers in medical facilities working in diagnostic and therapeutic nuclear medicine or of workers in nuclear power plants). Another potential source of exposure to certain types of radiation is accidental or intentional release of radioactive materials, as the result of an accident or of terrorist activity, e.g. as the result of a radiologic weapon such as a so-called “dirty-bomb.”
There remains a need in the art for improving patients in need of treatment of diseases related to oxidative stress affecting normal electron flow in the cells induced by chemical agents, radiation and/or disruptions in the transport of oxygen to tissues. The present inventors have unexpectedly discovered that administration of the compounds of this invention are effective in improving the outcome in patients that have been administered contrast media, have suffered from radiation exposure or suffer from hemoglobinopathy.